Novel Approach for Assessing Postinfarct Myocardial Injury and Inflammation Using Hybrid Somatostatin Receptor Positron Emission Tomography/Magnetic Resonance Imaging

ostinfarct inflammation and its resolution modulate ischemic injury after myocardial infarction (MI). While cardiac magnetic resonance imaging (MRI) is useful for assessing ventricular function, viability, and structural complications after MI, as well as detecting edema associated with acute inflammation, it lacks specificity for immune cell activity and may be less sensitive for identifying persistent, low-grade inflammation. Positron emission tomography (PET)

P ostinfarct inflammation and its resolution modulate ischemic injury after myocardial infarction (MI). While cardiac magnetic resonance imaging (MRI) is useful for assessing ventricular function, viability, and structural complications after MI, as well as detecting edema associated with acute inflammation, it lacks specificity for immune cell activity and may be less sensitive for identifying persistent, low-grade inflammation. Positron emission tomography (PET) imaging with 18 F-Fluorodeoxyglucose (FDG) and other more specifically targeted tracers could have a role for quantifying infarct-related inflammation and identifying a link with adverse myocardial remodeling. 1 Focal myocardial uptake of the SST 2 (somatostatin receptor 2) PET tracer 68 Ga-DOTATATE has been observed in patients with prior infarction 2 ; however, the clinical relevance of this finding remains unknown. Here, we report an illustrative case from an ongoing study aimed to evaluate a novel, integrated approach for assessing postinfarct myocardial injury and inflammation using hybrid SST 2 PET/MRI.
A 36-year-old man with no prior medical history or cardiovascular risk factors presented with severe, sudden-onset chest pain. Cardiorespiratory examination was normal. The ECG showed sinus rhythm with evolving inferior ST-segment elevation without reciprocal changes. He underwent primary percutaneous coronary intervention to an occluded obtuse marginal branch of the left circumflex artery ( Figure 1A and 1B). Reperfusion was achieved within 3 hours of symptom onset. Medical therapy with dual antiplatelet agents, a statin, beta-blocker, and angiotensin-converting enzyme inhibitor was initiated.
Initial blood tests showed a total cholesterol level of 5.4 mmol/L, with triglycerides of 2.49 mmol/L, and an LDL of 3.39 mmol/L. The total white cell count was elevated at 18.4x 10 9 /L, with a neutrophilia. The C-reactive protein level was normal at <3 mg/L and the peak hsTnI (high-sensitivity Troponin I) concentration was >25 000 ng/L (normal <58 ng/L). Echocardiography demonstrated normal left ventricular function overall with a biplane ejection fraction of 58%, akinesis of the basalto-mid inferolateral wall, and hypokinesis of the basal-tomid anterolateral wall.
The patient was enrolled in a multi-modality cardiac imaging research study (REGISTRATION: URL: https:// www.clinicaltrials.gov; Unique identifier: NCT04073810), involving serial 68 Ga-DOTATATE PET/MRI, cardiac MRI and CT coronary angiography with 2-year follow-up. Baseline PET/MRI was performed using a hybrid PET/ MRI scanner (SIGNA, GE Healthcare) on day 11 post-MI. Fifty minutes after an injection of 238 MBq 68 Ga-DOTATATE, PET images were acquired for 35-minutes in a cardiac bed position. Simultaneously acquired 3T MRI included 3-plane breath-held proton weighted, blood-suppressed single-shot fast-spin echo, 2D steadystate free precession cine imaging of the ventricles, T2-weighted edema imaging, T1 and T2 mapping, and late gadolinium enhancement. Static PET images were reconstructed from list mode data using iterative timeof-flight (256×256 matrix, Q.Clear b=350), and a freebreathing 2-point DIXON MR imaging sequence for attenuation correction.
Baseline MRI showed preserved left ventricular function, with persistent regional wall abnormalities (supplemental material: short-axis cine MRI acquired shortly after gadolinium contrast, Video S1). There was increased signal on T2-weighted imaging in the basal anterolateral, mid inferolateral, and apical lateral walls signifying edema, with corresponding areas of near fullthickness and sub-endocardial late gadolinium enhancement ( Figures 1C, 1F, and 2A). 68 Ga-DOTATATE PET demonstrated increased uptake (Figures 1E and 2G) in the infarct zone defined by late gadolinium enhancement and T1 mapping ( Figure 1D). The maximum Standardised Uptake Values (SUV max ) and Tissue-to-Background Ratios (TBR max ) normalized for blood-pool activity were 2.8 and 8.0, respectively, in the infarct versus 1.3 and 3.6 in the remote myocardium.
Over the following 3 months, the patient remained well. Follow-up PET/MRI performed 102 days post-MI using the same scanner and imaging protocol with an injected activity of 242 MBq showed a reduction, but not resolution, of the 68 Ga-DOTATATE PET signal (infarct SUV max 2.0; infarct TBR max 5.5; Figure 2H). Although there was no residual edema visible on T2-weighted MRI at follow-up ( Figure 2D and 2F) compared with baseline ( Figure 2C and 2E), quantitative T2 values were higher in the infarcted myocardium than remote region (infarct: 62 ms; remote: 51 ms; average noninfarct T2 value for scanner <53 ms; Figure 2B). In contrast to the abnormal PET and MRI findings consistent with ongoing myocardial inflammation, blood tests at day 102 showed normalization of hsTnI (15 ng/L from 206 ng/L) and reduction in NTproBNP (122 pg/mL from 362 pg/mL) levels, compared with day 11 values. High-sensitivity CRP remained low (0.27 mg/L from 0.69 mg/L). SST 2 PET imaging holds major promise as a novel marker of cardiovascular inflammation across several disease entities. SSTR2 gene expression is upregulated by macrophages stimulated in vitro, and the SST 2 receptor is co-expressed by CD68-positive macrophages in carotid endarterectomy specimens from stroke patients, 1 as well as endomyocardial biopsies from patients with cardiac sarcoidosis and myocarditis. 3 Unlike 18 F-FDG, somatostatin receptor PET tracers such as 68 Ga-DOTATATE have very low background activity in the healthy heart allowing for unhindered assessment of pathological myocardial inflammation without the need for dietary myocardial suppression. Indeed, clear infarctrelated 68 Ga-DOTATATE PET/CT uptake was observed in patients with both recent MI and chronic ischemic left ventricular dysfunction, in a post hoc analysis of the VISION study. 2 The mechanism of 64 Cu-DOTATATE binding to SST 2 receptors expressed by inflammatory macrophages within recently infarcted myocardial tissue has been shown in a mouse model, using a combination of in vivo PET/CT imaging and ex vivo radiometric and immunologic assays. 4 In that study, 64 Cu-DOTATATE uptake within cell-sorted macrophages from infarcted mouse myocardium was 3-fold higher than 18 F-FDG.
This imaging case report highlights a newly emerging molecular imaging method for interrogating specific components of the immune response to ischemic myocardial damage. In this instance, 68 Ga-DOTATATE PET uptake was closely colocalized with MRI features of recent MI, and later revealed residual inflammation that was not overtly visible on MRI, nor detected by blood biomarkers. Research is ongoing to confirm the cellular origins of post-MI 68 Ga-DOTATATE PET signal within inflamed and infarcted human myocardial tissue, and to test its association with longer-term ischemic myocardial remodeling. In the future, this approach could be clinically useful for informing the design and use of advanced immunomodulatory therapies for patients with chronic ischemic cardiomyopathy. LGE imaging was not repeated at follow-up.